Ask the Mito Doc – December 2024 Q&A

All answers today are based on personal experience of the participants. As always, please consult your personal physician prior to taking any action.

Clinicians:

• Amy Goldstein, MD, Children’s Hospital of Philadelphia
• Hilary Vernon, MD, PhD, Johns Hopkins University
• Matthew Snyder, MD, University of Virginia
• Russell Saneto, DO, PhD, Seattle Children’s Hospital

Q: Is a high protein diet good for mitochondria?

A: Matthew Snyder, MD: There isn’t a specific diet that is recommended for most individuals with mitochondrial disease other than a balanced, healthy diet.  Some individuals with seizures benefit from a ketogenic diet, but this depends on the specific mitochondrial disorder and should be guided by your neurology team.

Q: Ever hear that caffeine and or sugar can give a burst of energy in mito disease?

A: Matthew Snyder, MD: Caffeine and sugar give all of us a burst of energy.  Thankfully those with mito disease too.  I still recommend a balanced, healthy diet for all of us!

Q: What are the top five things I can do to reduce the number of MITO crashes that I have?

A: Hilary Vernon, MD: I think a lot of the things I’m going to say are easier said than done. Because we’re all busy people and we all have busy lives and it’s really difficult to modulate but, Sleep, hydration, and nutrition. Those are really the big three. Sleep, hydration, nutrition. Exercise in moderation for what’s best for you. And a good, varied diet, but I don’t really recommend any specific diet, just really a good mix of nutrients and no fasting. I recognize these things are a lot easier said than done and they’re things we all should be doing and very few of us actually do them.

A: Russel Saneto, DO, PhD: There have been some really interesting articles coming out of Nature Metabolism the last six months about exercises: exercise changes your metabolics. And the interesting thing is when they metabolomics together with deep sequencing, they find some genes that are altered. And with those genes, some of them are mitochondrial genes. Exercise as best you can in moderation but any exercise is good for you and it changes your mitochondria, changes your metabolism, makes things more efficient. And if you make your body more efficient at doing things, you use less energy.

Q: Are there ways for our patient families to keep themselves healthy during this terrible cold and flu season?

A: Hilary Vernon, MD: Get your vaccines, work with your doctor to get your vaccine safely, but get your vaccines. In crowded locations, I would probably recommend if you’re feeling up for it wearing a mask. And for people that you’re hanging out with over the holidays, request that if anybody is actively sick, they probably should stay home and get themselves better before infecting other people, which I also know is tough with family, but that would be my top 3.

Q: How can I be prepared in case I need to go to the ER?

A: Amy Goldstein, MD: That’s a great question. The first thing is that if you have an emergency letter from your doctor to try to have that with you most of the time. I encourage people to have that somewhere electronically, like have it on your cell phone or if it’s in your portal, know where to get it. If you’re going to a hospital where you frequently go hopefully they can pull that up in your records. One of the things that we found is that if you’re going to a hospital that’s not familiar with you, or even if it’s a hospital that is familiar with you, sometimes the letter does not always get read or it may be a doctor that’s not familiar with the fact that you have a letter.  The letter is there to help the ER staff be familiar with your care and what works and what doesn’t work. Ask to please page Dr. So-and-so because they can explain to you why my letter says this or that if you get the sense that they’re not listening, or you sense that the care isn’t going in the right direction. The other important thing is to make sure you have a list of all of your current medications and a list of all the specialists that you use. And try to have a sense of what you think is going on. One of the other things that happens on our end is, I have a lot of patients with different mitochondrial disorders and somebody might go to the emergency room and the big problem is just feeling lethargic or just like not feeling good, not feeling like themselves. And we really struggle with, what could be the problem? And this is really hard to sort out. We go through a long list: let’s check the blood work or are any of the electrolytes off. What about the blood count? Is there any sign of infection? Do we have to do a bunch of cultures? Do we have to do a chest x-ray? Okay, all of that is okay. Do we have to do an EEG? Do we have to do head imaging? Are we now worried about seizures or stroke-like episode? And hours are going by as we’re going through this long list of what could it be. Now we’re worried about the heart. Do we need to check an EKG? Does this person have a pacemaker? Is the pacemaker working? The problem has happened before and we figured out what it is and you have a sense of, oh, the last time this happened, it was a migraine and this is what worked. Or the last time this happened, it was because the calcium was really low so let’s check the calcium first, and then Endocrine has a plan. The last time this happened, this is what we did and this is what worked, because my patients know their disease much better than I do a lot of the time. And that goes for my patients with Kearns-Sayre syndrome, my patients with MELAS, patients with POLG, especially when the symptom is not very apparent. And again, in mitochondrial disease, sometimes the symptoms are really hard to describe. And it can be very hard to translate that to the doctor on the other end. So when you’re going to the ER, if it’s something that’s happened to you before and you have a really good sense of what it was, have your lists of specialists handy and how did we resolve it and what was the problem.

Q: What are the top 4 things that should be included in their ER letter?   

A: Amy Goldstein, MD: I’ve done a lot of work this past year individualizing those letters. My letter used to be the same for everybody. I realized this is not working. My letters are now different. If you have MELAS, it’s a very different letter than if you have POLG, and that’s a very different letter if you have Kearns-Sayre syndrome, and that’s a very different letter for Leigh syndrome, and there’s a very different letter if you struggle with lactic acidosis. So my letters are now very individualized because they have to be. And I’ll even put on there, this patient’s neurologist is Dr. So-and-so, call this number. So they become very, very individualized. I will also say that not everybody has an ER letter. I give an ER letter when it’s somebody that I know needs to go to the ER for very specific reasons and I want the ER to know exactly what to do so that we’re not losing time. So that we can make sure that the ER has a really good strategy for who they should be calling and what the emergency is going to be.

Q: What is the Mito cocktail, and where can I get it?

A: Russell Saneto, DO, PhD: Dr. Bruce Cohen and I would argue about 25 years ago, and we had no treatments for mitochondrial disease, and there were some themes in the research realm that antioxidants might be helpful, and every now and then a patient would come by and tell us the benefit from taking a particular antioxidant. There’s been no real clinical trials with any of them. I don’t use a particular standard cocktail per se, and I don’t think any of us do anymore. So my take on the vitamin cocktail is that it’s in the vocabulary of mitochondrial disease. There is some good data from CHOP looking at complex 1 and certain supplements. I tend to follow that for my patients who may have a complex 1 problem. I would use 4-Aminopyridine in some of the Mito patients with cerebellar ataxia, I find that it’s worked pretty well. And also there are about 12 different vitamins or cofactors that have genetic deficits, that if you supplement those disorders, they can be beneficial, and that’s been well vetted in the literature. They’re rare, though.

A: Matthew Snyder, MD: I think my approach is somewhat similar to Dr. Saneto’s but we try to just give the option to patients, and families, and say, we don’t have much deep evidence that some of these will work but if the harm is quite low I encourage them to try it. And with the caveat of knowing that if there is no perceived benefit after a defined amount of time, I try to really follow my patients closely and say, let’s check in every 3 or 6 months, and we’re either increasing the dose of something or adding something else, or we’re taking something off, because I don’t want you to continue to spend money on something that might not be working.

A: Hilary Vernon, MD: The cocktail is very disease specific and disease dependent because there is very good evidence in a subset of disorders. So I don’t want to put a blanket policy across things, and I tend to be a bit of a fence sitter. I think that I don’t like levels of things that we know are important to run low. So if carnitine is low, if coenzyme Q10 is low, if vitamin E is low, I like to get those things well within the normal range, but I don’t know that there’s any known benefit to running things super therapeutic. So in that sense, I would like to see vitamins in a healthy range and vitamins that we know they’re important, but not to go too overboard.

Q: How do you test for the different levels of Vitamins, Is there a panel or is there a specific one-off test that you give?  

A: Russel Saneto, DO, PhD: There are particular labs across the nation that do vitamin testing. Our lab in Seattle does them all. I usually call them and ask if I am looking for a particular deficiency i.e. patient may have a riboflavin transporter deficiency. I just want to check to see if I need to add this or that.       

Q: Is it possible for a child with mitochondrial disease to have a mild malignant hyperthermia reaction related to anesthesia? Or is the reaction always severe if present? And if the child had a reaction to anesthesia should there be any additional precautions taken the next time they need to undergo anesthesia?

A: Amy Goldstein, MD: Malignant hyperthermia is usually due to RYR1 gene and not a mito issue but mito can cause abnormal response to anesthesia so if there was any problem you can request to speak to anesthesia prior to any future procedure to review and request that anesthesia precautions for mito disease are utilized.

Q: What is the definition of Mitochondrial Disease? I was diagnosed with Mitochondrial myopathy 18 years ago thru a fresh muscle biopsy with findings of ragged red fibers as well as complex 1 and 3 deficiency and fewer numbers of normally functioning mitochondrial. Just recently, my Genetics doctor has informed me that he doesn’t believe I have Mito as muscle biopsies are now considered to be obsolete. So, the question becomes, does a diagnosis such as the one I was given justify a diagnosis of mitochondrial myopathy/disease?

A: Amy Goldstein, MD: Muscle biopsy is not obsolete but what is important is to have a genetic diagnosis to see why you have an abnormal muscle biopsy. Have you had updated genetic testing such as exome or genome sequencing? Was your muscle ever tested for mito DNA sequencing? There are secondary causes for what was seen on your muscle biopsy as well.

Q: I got my whole genome, whole exome sequencing back and they didn’t find anything. What do I do next?

A: Matthew Snyder, MD: It depends on your individual situation. Like Dr. Vernon was saying, we do genetic testing to try to figure out if there is a specific disorder that we know that we can treat, or we can follow your care closely; can we define this condition for you? We don’t want to be treating the wrong condition. So that’s why in this era now, we are promoting genetic testing, broad genetic testing really is the front line. And that’s what whole exome and whole genome sequencing are designed to do because they’re much less invasive tests than what we had decades ago or even just years ago. The next steps are, if I’m or we are really suspicious that you still have a primary mitochondrial disorder, we can take a research genetic approach and contact labs that are doing more higher, even higher order genetic testing like long read, whole genome sequencing and optical genome mapping. Things like this will probably become more available in the coming years. And then also taking the approach of taking a targeted testing at the muscle level. If you’re affected by a myopathy or even not a myopathy, we can do a skin or muscle biopsy and then do essentially what we call functional testing where we put the mitochondria to the test. We look at them under a microscope and test them to see how well they are working. There can be downsides to that. Then we can also do genetic testing of the muscle tissue itself. So just like we do the mitochondrial DNA testing of the buccal cells, we can do that testing as well in the muscles because of heteroplasmy and the variable mitochondrial DNA changes that can occur in different tissues. We also can do biochemical testing: Are there different biochemical patterns that would really make me suspicious that this is a primary mitochondrial disorder?

A: Russel Saneto, DO, PhD: But just to let you know, sometimes you don’t get a result. And I think that was one of the questions. And you kind of think well, maybe it’s all in my head and I don’t have disease. Let me give you the primary example of that science; the wheels of science move slow, but they do move. So 15 years ago the only thing available to us was muscle biopsy testing, limited gene testing and some biochemistries. So I have this brother and sister well known to the UMDF, the sister anyway. And we got a complex 1/3 with a little bit of complex 4 deficiencies and I was poo-pooed. Chuck Hoppel did the assay, so I was convinced they were correct, and we waited. Genetic testing came out, I sent everything we could. We waited. This was 12 -13 years ago, and seven months ago, we got a genetic hit and we found their gene! Not only did we find their gene but we found two other kids, actually adults.

And now I’ve just finished help writing an IND for a therapy for these four patients. Yeah, guanine uridine kinase 1.

Q: Have neuropathic pain medications, such as amitriptyline and gabapentin, been shown to reduce symptoms in either primary or secondary mitochondrial diseases?

A: Amy Goldstein, MD: Absolutely, they can be helpful to treat these symptoms.

Q: My 20 year old daughter was very regular with her menstrual cycle until this year, now she has only had 2-3 periods. Her cortisol levels have tested low, so her endocrinologist has scheduled a 2 hour test to check her cortisol level.  I believe she is being tested for autoimmune diseases.  Is there anything that I need to be cautious on with this testing or medicine that may be prescribed?  Is it related to her mito? Her health has been stable since her Thyroid was removed in 2015.  Just being cautious and one step ahead if possible.

A: Amy Goldstein, MD: This testing is very important to figure out both why she is having secondary amenorrhea (lack of periods) and her cortisol levels as adrenal insufficiency can be dangerous but treatable! Endocrine is doing a great job investigating. Is she on good thyroid replacement?

Q: How long before other mito symptoms such as depression can show up?

A: Matthew Snyder, MD: Unfortunately it is really hard to predict when symptoms will show up and which symptoms will show up.  Not all patients will develop mental health issues, but many do.

Q: There are a lot of children’s (mito) doctors. I’m having such a hard time finding an adult doctor that will actually listen to me. They all just brush me off.     

A: Matthew Snyder, MD: I’m sorry to hear this. Hopefully you can find a provider in your state or region that can see you from the UMDF website.  If not, many geneticist and neurologists will see adults (though not all are comfortable with mitochondrial disease).  I hope you can find answers!

Q: What is an ER letter and how do I get it? And what is the airport letter?   

A: Matthew Snyder, MD: ER letters help guide emergency room teams in how to properly take care of an individual with primary mitochondrial disease who presents to the ER.  This can include a description of what the baseline health level is, what to expect from the specific condition, and what labs/imaging studies/treatments should be given if a patient is sick, having seizures, etc. As Dr. Goldstein said, not all individuals need one of these letters.  The mitochondrial team/physician should provide you with one if needed.

Q: Are there any trials for NARP syndrome….deletion of mt-atp 6 gene? 

A: Amy Goldstein, MD: There will be trials coming; depends on the age of the patient as well as phenotype (Leigh syndrome or NARP). Is it a deletion or a point mutation?

Q: Is it normal for mito kid’s bicarb to run really low? This is new for us but been months.

A: Matthew Snyder, MD: Yes this is normal and should be treated.

Q: Do you have a recommendation on trials in MDMD, nDNA, RRM2B, as UCB is linked with many of you and UMDF.

A: Amy Goldstein, MD: RRM2B was one of the genes for the Stealth elamipretide trial; stay tuned for results of the latest trial which will be released early 2025! Hopefully it will prove efficacious and be approved for these genes.

Q: Which genes on the mtDNA maintenance defects do you think could be next included in the nucleosides therapies, after TK2, following that path? (RRM2B, POLG, TWINKLE, TOP3, …?) 

A: Amy Goldstein, MD: We know the trial in Canada recruited patients with several of these defects but we haven’t seen all the data; some make sense and some do not.

Q: For immigrant patients that were first diagnosed abroad and now live permanently in the US what advice do you have for them in order to better manage their mitochondrial disease especially if they have a treatment plan given by their doctor abroad? Do they need to go through the stressful diagnosis process again?

A: Amy Goldstein, MD: No, bring your records with you to your appointment and we can pick up from there. If there is not a definite diagnosis (you) may need more testing. The US does things a little differently than other countries but we all know each other very well and can contact each other. We’re very familiar of looking at records from abroad due to international patient’s second opinions. I don’t see this as a problem.

Q: I understand that heteroplasmy levels in blood and buccal cells are considered below typical thresholds for MT-TH mutations to cause symptoms. However, given our son’s complex presentation and genetic findings, I’m trying to understand the potential role of low heteroplasmy (buccal 3% and blood 2%) combined with his FBXL4 variant. Is it possible that even low heteroplasmy, combined with his nuclear gene variant, creates a cumulative impact on mitochondrial function?      

A: Amy Goldstein MD: Has any other tissue been tested such as urine or muscle? Levels can be higher in other tissue and could then be more relevant and significant. FBXL4 is autosomal recessive and so you need to have 2 mutations to have this condition.

Q: Can people with Mitochondria dysfunction have morning sickness?

A: Amy Goldstein MD: Yes this can be seen in mito; would go to GI as there could be many possible causes.

Q: What should a family do when they are traveling for the holidays?

A: Amy Goldstein, MD: Depending on where you are going, we can identify the local mito docs, even if it’s Europe, we now know where our colleagues are in the world. Whether you’re going to Barcelona or Poland or Florida, we can look up providers, we can have a backup plan.

A: Russell Saneto, DO, PhD: And to take their emergency letter on the airplane with them.

A: UMDF Support/Margaret: And the UMDF will help families when they’re traveling to identify physicians in their area. I just did one for France the other day. So it is important to think those things through. What if I’m away and something happens?                          .

And there are special programs at most airports that will help people with disabilities move through the airport more smoothly and people should definitely take advantage of that.

Q: Dr. Vernon, can you tell us about the ADCOM?

A: Hillary Vernon MD PHD: The FDA’s Advisory Committees (ADCOMs) are groups of outside experts who provide independent advice on drugs, medical devices, biological products, and food. ADCOMs evaluate the safety and effectiveness of therapies, and make recommendations to the FDA on whether to approve or disapprove marketing applications. The FDA makes the final decision.

This was the ADCOM to look for advice on the approval of elamipretide for the treatment of Barth syndrome. One thing to know is that the FDA has not yet rendered a decision on elamipretide for Barth syndrome, and they don’t have to agree with the ADCOM. Usually they do, but they’re not bound to it. So I just want to get ahead of that a little bit. But my impression is when the FDA convenes an ADCOM for a potential therapeutic it’s because they either don’t really have the internal expertise to definitively judge that product, or there’s too much debate within a given division about whether or not they want to say yes or no. So I think a few things happened that led to the Adcom for elamipretide for Barth syndrome. But just to say, what happens is when an FDA division can’t within themselves make a decision about whether or not they want to vote yes or no on a drug, they convene a panel of experts and that panel can range anywhere from, I believe, 8 to 16 people. The one for Barth syndrome was quite large. And they try to bring together people who are not involved in the drug development itself, but have some knowledge in the area. In our case, it was mitochondrial disease, heart disease, a lot of statistical people, and people with just general knowledge. A community advocate was also there. And then what happens is the FDA essentially presents where they stand in terms of their thoughts on the agent, why they felt that they couldn’t go ahead immediately with approval; where they were having a little bit of trouble making a decision. Then the developers of the drug or whoever has filed for the new drug application, sometimes it’s an academic group, sometimes it’s a pharmaceutical group, sometimes it’s a combination like ours was, presents the case for what is the evidence for the drug being potentially beneficial. Then there’s kind of an open session where families and physicians have the opportunity to express their experience with the disease, their experience with the drug, their experience with treating the disease. Then there’s a big debate process, which is extremely stressful because you’re sitting there listening to debates going back and forth and sometimes things are said that you feel aren’t correct. You can’t jump in and say anything. You just have to let it ride out. And then a vote taken. And the nice thing about the vote is that among the panel it’s done anonymously. So each person is not influenced by the vote from the person before them. And then at the end, everybody expresses why they voted the way they did. And this did go in favor of approval for elamipretide. And at times, I have to say, I thought that was a little dicey because the conversation got a little heated. So now we’re kind of in a holding pattern until the FDA makes their decision.

I’ll editorialize a little bit about why I think this ended up going to an advisory committee rather than directly being approved or not by the division; it’s because the specific division that we were in was the cardiorenal division and they’re not used to dealing with the clinical trials and ultra-rare diseases. So the Barth syndrome trial looked at the effectiveness of elamipretide in 12 patients and that was really, really hard for that division to wrap their heads around a trial that was in 12 patients rather than 10,000, which is more what they’re used to so there had to be a lot of education that was a big part of the process of the Adcom.

One other thing I might editorialize after having gone through all of this, one of the most common and frequent talks I’m giving now is to other investigators who are about to go through this process.

Q: Dr. Goldstein, you presented at the 2024 Mito Med Conference during the mental health track, can you tell me a little bit about what that was like and what were some of your takeaways from what you learned from our patient families?

A: Amy Goldstein, MD: Yes, thank you. So I had the opportunity to talk about that a few times during the symposium. I gave a talk to the patients and families and then I gave a talk during the scientific session. During the scientific session, I spoke along with several other people Ana Andriaza from Canada and some of the other colleagues that I was with and it was a really fascinating panel. One of the things that I enjoyed most was preparing for the talk because I had to do a lot of background research into how many times different neuropsychiatric problems were reported in mitochondrial patients. And what I discovered in preparing for the talk was that we really don’t emphasize it and talk about it in my opinion enough when we’re talking with our patients. And when we do, I think we assume or we think that, well of course you have anxiety, look at all the symptoms you have, or of course you’re sad because look at all the symptoms you have. And this is what I’ve always thought – that the situation is depressing or it seems depressing. But to learn that people with mitochondrial disease may experience anxiety and depression up to 10 years before their other symptoms emerge and that it’s actually part of the brain’s symptoms, just like seizures can be, just like stroke-like episodes can be, for me that was fascinating. And to learn how integral it is to diseases like MELAS, like POLG, and then to go look at my POLG cohort of teenagers with POLG, a lot of them were diagnosed with bipolar disorder prior to their POLG disorder. And some of these children and adolescents did get into trouble because they were put on medications that aren’t good for this disorder because they had the psychiatric symptoms first before they had epilepsy. This is how some of these kids got into trouble with liver disease and things like that. It made me realize how much more closely we need to be working with our psychiatric colleagues to make sure that they’re aware of mitochondrial disease. Especially when they’re treating them, especially when the psychiatric symptoms can come up first before any other manifestations of mito. So that was really what impressed me. The numbers are huge, anywhere from 25 to 75% of people with mitochondrial disease have psychiatric manifestations. So it’s very, very high. And it’s not just situational. It’s not because you’re dealing with all the other symptoms of mito. It’s part of the condition in many of the patients that have especially the central nervous system manifestations. And then the other thing that came up, especially from some of the other speakers was, what does that mean in terms of medication? And this comes up no matter what we’re talking about, what medications are safe. And we always have two parallel conversations: what medications are safe and are any medications safe. And these always run in parallel because when you put drugs in a dish with mitochondria, none of them are safe. But when you put drugs in humans that have mitochondria, within reason, almost everything we use is safe, except you can’t use Depakote if you have POLG. We all know that.

And again, when you put drugs in a dish with mitochondria, many drugs are mito-toxic. And a lot of things that we learned 23 years ago that we all memorize is, you never want to use this drug or that drug or this drug or that drug. The list of drugs that we told patients not to use got completely out of control. And we all as doctors saw that our patients were being harmed by this list. There are people that still walk around saying, I’m allergic to XYZ and this and that and they don’t take antibiotics and they won’t use this and that. And that is very different than if somebody has taken a drug and had a bad reaction. That is absolutely fair and don’t use that drug. But we don’t want people to have a list memorized of drugs they should never take because somebody told them it’s bad for their mitochondria.

And so we still have a lot of unlearning to do and try to have our patients have an open mind to trying different medications, especially if you’re suffering. So my point of this long-winded answer is if you’re suffering from anxiety and depression, many of these medications are safe to try, just like if you have an infection, many antibiotics are safe to use. We don’t want anyone dying from an infection because you’re afraid to use an antibiotic. But knowing that the mitochondria were at one point in time bacteria, yes, any antibiotic is designed to destroy the mitochondria, but that doesn’t mean that the antibiotics are going to damage you, right? They’re still safe to use in an infection. So there were many, many talks and many conversations that were had about medications. And I think that’s kind of our next foray into this field is making sure that we know exactly what medications we want to use. And it really also skirts on the whole topic of genetic testing because when we are now counseling our patients for whole genome sequencing, one of the things that a lot of the companies are offering is something called pharmacogenomics. How do our patients metabolize different medications? A lot of our patients are really into that. They want to hear, what medication would be best for me and how do I metabolize this drug and that drug? Because they want to learn more about their response and what medicine would be best. So that part interests me a lot. I want to make sure people have their symptoms treated.

Because the best thing that we can do for our patients right now is optimize their health to the best of our ability, that means we’re treating every symptom that we can. 2025 is going to be a big year for clinical trials, lots of things are happening. We’re going to have more trials. We want everyone’s health optimized to the best that we can so that we have people ready to go for clinical trials.            

Q:  What really excited you for the mitochondrial disease community in 2024 and what are you looking forward to?

A: Hilary Vernon, MD: I’m going to echo what Dr. Snyder said, and I think also what Dr. Saneto said as well, which is really the enthusiasm of the community. Everybody’s really fired up about the possibility of new therapeutics. There’s a lot coming up. It’s a very exciting time. And for those of us who have been in the field for quite a while or have been dealing with these diseases for quite a while, it feels like there’s a lot of momentum right now. And so I think it’s a very exciting time.

A: Amy Goldstein MD:  There was a really nice paper that came out this past year from the European group about treating seizures in mitochondrial disease. Michelangelo Mancusto is the lead author on that paper and it’s a beautiful article and graphics. I pull it out all the time. I can tell you that when I’m in the ICU it has helped me tremendously. What I really do when I have a kid in status is, I email Russ (Saneto). We both were on an email that went around the world in the past 24 hours, I think about 10 of us were on it. Each person had a different answer. When we go to meetings this is the kind of stuff that I want to be able to get together with my colleagues and say, What are we doing? You know we still have a serious problem. And this is what I look forward to at the meetings. We want to hear about all the science, we want to hear about all the clinical trials. But what I really want to do is get in a room with my colleagues and say, what are you doing when you’ve got a patient in trouble? What tricks am I not using that you’re using? And can I still email you when I’m in big trouble?

A: Matthew Snyder, MD: I think that just the opportunity to make more deep connections with families and, hopefully, as you guys all are aware on this call, there aren’t clear ways to take care of you or your child in every situation. And we are relying on the help of our colleagues and your help as well. Being able to partner with families is the reason I’m in genetics and metabolism and now I’m siphoning down to mitochondrial disease and I’m excited. When I look back on 2024, some of the biggest moments in my line of work were the conversations I got to have with families and thinking through hard problems and also hard situations. Looking forward to 2025, I’m excited to meet more families when we’re on the cusp of a lot of exciting things in our field.

A: Russell Saneto, DO, PhD: I’m going to be really happy when the FDA rules on DCA. Treatment is something that we really need in mitochondrial disease. There are so many different, over 350 different genes, and probably at least 175 – 200 different permutations of disease and we try to knock one disease off at a time when we find a good treatment for it. And Therapies! I’m really excited about 2025, because I think that this whole idea of limited oxygen in mitochondrial disease treatment is probably valid. Dr. Vamsi Mootha is really doing some wonderful work on that. And we’ve sort of seen it in the Leigh Syndrome mouse as well with breathing. Dr. Mootha’s got a small molecule that he’s working on for Friedreich’s ataxia that I think will be exciting. I think it’s going to be a robust year. What I’m really hoping for, though, is I think there are markers for defining certain mitochondrial diseases in the newborn screen. Prediction of mitochondrial disease would be another wonderful thing to know, plus, say, a more widespread treatment for particular types of mitochondrial disease that we can use, that we can take from the bench to the clinic would be another aim. You know, if you don’t shoot for the stars you’ll never reach the the blueness of the sky. I think we need to be optimistic and hopeful and keep moving the wheels of science downhill.